Approximately 22 million people in the US suffer from asthma (National Heart, Lung, and Blood Institute). As a result, the annual economic cost of asthma is $19.7 billion. Globally, an estimated 300 million people worldwide have asthma, with 250,000 annual deaths attributed to the disease, and the prevalence continues to increase. By 2025, the number of people with asthma is estimated to grow to more than 400 million. Asthma is a respiratory condition in which the airways become inflamed and constrict, usually in response to one or more environmental triggers. When an asthma attack occurs, the muscles surrounding the airways become constricted and the lining of the air passages swells, reducing the amount of air that can pass to the lungs. In highly asthmatic people, breathing in an allergic substance, or allergen, can induce symptoms. Current treatments for asthma are associated with blocking or inhibiting an asthma attack and subsequent air passage swelling. The most successful drugs on the market combine long-acting beta-agonists (LABAs) with steroids, and include Advair, Symbicort and Duleral. While these are somewhat effective at managing asthma symptoms, the effects are temporary, have many side-effects, and require daily administration. Desensitization protocols exist, but are intensive and impractical given the fact that most asthmatics have multiple, often unidentified, allergens. A natural therapeutic that promotes asthma regression through a clearly defined, novel mechanism would provide profound medical advancement in treatment of asthma. The goal of these studies is to advance a new tolerance-inducing therapeutic, called HH-10, toward the clinic to treat patients with asthma. Recently, we demonstrated that HH-10 acts as a tolerance-inducing therapeutic by promoting the induction of IL-10 producing regulatory T cells (TR1) from conventional antigen-specific memory T cells. The aims of the proposed studies are to: 1) confirm in an airway hypersensitivity mouse model that inhaled administration of HH-10 regresses airway hypersensitivity and to identify the effective HH-10 dosing for future pre-clinical studies; and 2) examine potential in vivo toxicity and side-effects associated with HH-10 treatment, providing data that effective dosing concentrations demonstrate no or minimal side effects. PUBLIC HEALTH RELEVANCE: Current therapeutic treatments for asthma target symptoms. This project aims to develop a tolerance-inducing therapeutic that promotes asthma regression through a novel mechanism. Success would ultimately provide a profound medical advancement in treatment of asthma, a significant benefit to human health, and a dramatic reduction in the economic impact of asthma in the US and globally.